Alptekin, A. | Search bioRxiv

bioRxiv2021

Pulsed Focal ultrasound as a non-invasive method to deliver exosomes in the brain/stroke

Exosomes, a component of extracellular vesicles are shown to carry important small RNAs, mRNAs, protein, and bioactive lipid from parent cells and are found in most biological fluids. Investigators have demonstrated the importance of mesenchymal stem cells (MSCs) derived exosomes in repairing stroke lesions. However, exosomes from endothelial progenitor cells (EPCs) have not been tested in any stroke model nor has there been an evaluation of whether these exosomes target/home to areas of pathology. Targeted delivery of IV administered exosomes has been a great challenge and a targeted delivery system is lacking to deliver naive (unmodified) exosomes from EPCs to the site of interest. Pulsed focused ultrasound (pFUS) is being used for therapeutic and experimental purposes. There has not been any report showing the use of pulsed low-intensity pFUS to deliver exosomes to the site of interest in models of stroke. In this proof of principle study, we have shown different parameters of pFUS to deliver exosomes in the intact and stroke brain with or without IV administration of nanobubbles. The study results showed that administration of nanobubbles is detrimental to the brain structures (micro bleeding and white matter destruction) at peak negative pressure (PNP) of >0.25 MPa, despite enhanced delivery of IV administered exosomes. However, without nanobubbles, pFUS PNP = 1 to 2 MPa enhances the delivery of exosomes in the stroke area without altering the brain structures.

neuroscience↗

bioRxiv2019

Generation of novel diagnostic and therapeutic exosomes to detect and deplete pro-tumorigenic M2-macrophages.

Given their pro-tumorigenic function and prevalence in most malignant tumors with lower survival, early detection and intervention of CD206-positive M2-macrophages may boost the clinical outcome. To determine in vivo distribution of M2-macrophages, we adopted 111In-oxine-based radiolabeling of the targeted exosomes. When injected these radiolabeled targeted exosomes into breast tumor-bearing mice, exosomes accumulated at the periphery of the primary tumor, metastatic foci in the lungs, spleen, and liver. Ex vivo quantification of radioactivity also showed similar distribution. Injected DiI dye-labeled exosomes into the same mice showed adherence of exosomes to the CD206-positive M2-macrophages on ex vivo fluorescent microscopy imaging. In addition, we utilized these engineered exosomes to carry the Fc portion of IgG2b with the intention of augmenting antibody-dependent cell-mediated cytotoxicity. We have auspiciously demonstrated that M2-macrophage targeting therapeutic exosomes deplete M2-macrophages both in vitro and in vivo, and reduce tumor burden increasing survival in a metastatic breast cancer model.

cancer biology↗